A 900 compound nitroimidazole-based library derived from our pretomanid backup program with TB Alliance was screened for utility against human African trypanosomiasis (HAT) by the Drugs for Neglected Diseases initiative. Potent hits included 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides, which surprisingly displayed good metabolic stability and excellent cell permeability. Following comprehensive mouse pharmacokinetic assessments on four hits and determination of the most active chiral form, a thiazine oxide counterpart of pretomanid (24) was identified as the best lead. With once daily oral dosing, this compound delivered complete cures in an acute infection mouse model of HAT and increased survival times in a stage 2 model, implying the need for more prolonged CNS exposure. In preliminary SAR findings, antitrypanosomal activity was reduced by removal of the benzylic methylene but enhanced through a phenylpyridine-based side chain, providing important direction for future studies.

我们通过与TB Alliance的拟痛前备份计划衍生的900种基于硝基咪唑的化合物库，被《被忽视疾病药物》计划筛选出了针对人类非洲锥虫病（HAT）的实用性。有效的命中物包括2-硝基-6,7-二氢-5 H-咪唑并[ 2,1- b ] [1,3]噻嗪8-氧化物，令人惊讶地显示出良好的代谢稳定性和出色的细胞通透性。在对四次点击进行了全面的小鼠药代动力学评估并确定了最活跃的手性形式后，苯丙氨酸甲酯的前体氧化物的噻嗪氧化物对应物（24）被确定为最佳销售线索。每天口服一次，这种化合物可以在HAT的急性感染小鼠模型中完全治愈，并且在2期模型中可以延长生存时间，这意味着需要更长的CNS暴露时间。在SAR的初步发现中，通过去除苄基亚甲基可以降低抗锥虫的活性，但是通过基于苯基吡啶的侧链可以增强抗胰蛋白酶的活性，这为将来的研究提供了重要的方向。